Porous hollow fibre membranes are examples of porous affinity membranes having a blood side and a filtrate side. Such membranes are well known for analytical, diagnostic or therapeutical purposes. For example, such porous hollow fibre membranes are useful for the treatment of blood or other biologically active fluids with a view to eliminating undesired compounds therefrom, i.e. in therapeutic apheresis. Porous hollow fibre membranes are normally composed of a bundle of separate microporous hollow fibres. For detoxification of whole blood, e.g. dialysis and plasmapheresis, the membrane bundle is normally potted at each end of a polycarbonate tube fitted with two ports in a shell. The blood is normally extracorporeally pumped through a lumen representing the blood side, of each fibre, and a part of the blood plasma penetrates, i.e. is filtrated, through the pores of the fibre wall into an outer compartment representing the filtrate side, surrounding each fibre in the bundle. The concentrated blood containing blood cells, too large to enter the pores, and the remaining non-filtered part of blood plasma passes through the lumen. In a venous blood line the filtrated blood plasma stream is normally added to the non-filtered blood stream and returned to the patient.
With a view to eliminating undesired compounds from the blood, the surfaces and pores of the porous hollow fibre membranes are provided with activated sites or ligands specific for binding to the undesired blood compounds to be eliminated. Such activated sites or ligands are normally based on or bound to functional groups, e.g. amino, carboxy, or sulfonic acid groups, on the porous membrane surface. The undesired compounds to be eliminated from the blood are normally toxins of different kinds, e.g. bacterially derived toxins. Further examples of such undesired compounds are presented below.
The lumen surfaces on the blood side of microporous hollow fibre membranes, the surfaces of the pores and the surfaces on the filtrate side of such membranes are often provided with such activated sites or ligands, particularly for purification of blood or biologically active fluids.
In blood purification applications activated sites or ligands, e.g. positive amino groups as functional groups for heparin or endotoxin adsorption, on the surface on the blood side of such membranes may activate certain blood constituents, e.g. thrombocytes. In such a case, these blood constituents are activated and/or adhered to the ligands and are significantly reduced from the blood. Such an adhesion is undesired. Other blood constituents, e.g. leucocytes, red blood cells and proteins, may to some extent also be adhered to such ligands or activated sites on the blood side of the membrane.
This undesired activation of blood constituents in such membranes has since long been a great problem, in particular the accompanying undesired elimination of thrombocytes from the blood. Several attempts have been made to solve this problem to prepare microporous hollow fibre membranes lacking the above-mentioned ligands or activated sites on the blood side of the membrane, but so far only complicated processes requiring large amounts of reaction chemicals and solvents have been found. Moreover, these processes are also expensive, ineffective and not environmentally friendly, thereby creating problems highly needed to solve.
The type of materials used in such membrane products is determined by cost and their thermomechanical properties. In many cases the corresponding physico-chemical surface compositions are not suitable for appropriate system integration, or these do not fit to the desired interaction with a contacting solid, liquid or gaseous counterpart. In these cases chemical surface modification is applied to establish a special surface functionality. The conventional techniques used are wet chemical ones, as mentioned above and, more frequently and preferably, gase phase reactions like plasma glow discharge. The latter technique is advantageous, especially in case of polymer materials, because the highly reactive plasma species, which are easily generated from low molecular weight functional precursors under glow discharge conditions, can modify the relatively inert polymer surfaces, and no strong acids or alkali, affording waste removal, are necessary. Plasma or glow discharge treatment techniques are disclosed in numerous publications, for instance in J. R. Hollahan and A. T. Bell: “Techniques and applications of plasma chemistry”, Wiley N.Y. 1974, or H. Yasuda, J. Macromolecular Sci. Chem. A 10, 383 (1976), as well as in WO 03/090910 (Gambro Lundia AB). In principle there are two routes to modify surfaces using plasma. The first one is performed under ambient pressure, where barrier discharges may be excited. In these cases very often only oxidation is achieved. Principally the result is a more inhomogeneous surface activation, thermal effects are observed and relatively heterogeneous chemical surface compositions are predominant. The second route is performed at a low pressure in the range between 0.05 mbar and 10 mbar using high frequency excitation like 13.56 MHz, where only the electrons are accelerated towards very high temperatures, but the molecular and atomic species achieve only a very slight increase in temperature. Under such plasma conditions, a much higher quality of surface finish is obtained, thermal effects can be neglected, adsorbed contaminating layers are desorbed or can be etched and well defined layers of hydrophobic characterisitics or thin and stable surface modifications with functionally or chemically reactive groups like carboxyl-, amino-, or hydroxyl- can be generated. Respective reviews have been published in J. Phys. D, App. Phys. 34, 2761-2768 (2001) by M. J. Shelton and G. C. Stevens, by Jonathan M. Kelly, Robert D. Short, Morgan R. Aleander: “Experimental evidence of a relationship between monomer plasma residence time and carboxyl group retention in acrylic acid plasma polymer”, Polymer, 44, 3173-3176 (2003), by William G. Pitt: “Fabrication of a Continuous Wettability Gradient by Radio Frequency Plasma Discharge” Journal of Colloid and Interface Science 133 (1), 223-227 (1989), C. G. Gölander, M. W. Rutland, D. L. Johansson, H. Ringblom, S. Jönsson and K. Yasuda: “Structure and Surface Properties of Diaminocyclohexane Plasma Polymer Films”, Journal of Applied Polymer Science 49. 39-41 (1993), and in Patent WO 03/090910 A1.
An atmospheric pressure plasma process can be easily integrated into any continuous production line without investment into vacuum equipment. But this advantage is basically accompanied by lower quality in the resulting surface finish. In case of the low pressure glow discharge technique, the higher surface finish quality requires extra pumping units and vacuum vessels. The material to process has to be incorporated into the vacuum equipment in advance and collected after processing in a special area of the-closed vacuum system, but a good quality of surface functionalisation without thermal effects may be achieved.
Further, the low pressure plasma processing is basically realized in a batch-like manner restricting the integration into other consecutive production steps. Proposals to overcome this limitation are the subject matter of several patents, for instance U.S. Pat. Nos. 5,314,539, 6,250,222 and GB 2,084,264 concerning plasma or vacuum treatment of flat materials like foils or photographic films, and U.S. Pat. No. 3,952,568 for the vacuum processing of rod, wire or strip materials. The basis of all these constructions is a sequential reduction of pressure using a series of drive rollers contacting the substrate surface (flat material), or dies with an opening not more than 0.2 mm larger than the diameter of the respective rod or wire (circular material) and a surface finish of the rollers or dies to minimize friction, separated by pumping chambers.
None of these patents excludes porous materials as substrates which, due to their low mechanical strength, high void volume and inner surface area, may lead to the problem of an intense transport of air into the vacuum system. These types of material are widely used in separation technology and medical analytic systems or as catalysts. In addition to their defined pore size in many applications, their wettability has to be improved, a special chemistry of the inner pore surface is necessary or a very thin film with tailored permeability characteristics towards gases or solvents has to be added. The chemical modification of these types of substrates, especially of the inner porous structure using low pressure plasma, is a topic of the U.S. Pat. Nos. 5,798,261 and 6,022,902. Plasma polymerisation onto porous membrane structures for the development of gas separation, vapour removal and fluid separation has been widely investigated, see ref. M. Yamamoto, J. Sakata, M. Hirai: “Plasma polymerized membranes and gas permeability”, J. Appl. Polym. Sci, 29, 2981-2987 (1984) or T. Hirotsu, S. Nakayima: “Water-ethanol permseparation by pervaporation through plasma graft copolymeric membranes of acrylic acid and acrylamide”, J. Appl. Polym. Sci. 36, 177-189 (1988).
Thus, air to air plasma surface modification at low pressure of wires, tubes, rods, fibers is known within the state of the art. If the outer surface of a tube or hollow fibre is to be modified, then the gas in the fibre lumen may not interfere with the plasma, which is circumferential around the tube or hollow fibre. Especially, when the lumen is smaller than about 1 mm, there will be no plasma ignition in the lumen because at the low pressure mode the mean free path length of the gas molecules is too long. In the case of a hollow fibre structure with a large pore size and a high porosity, you need just to exhaust the air flow entering the entrance hole of the hollow fibre into the vacuum. The diffusion of gas out of the lumen will not significantly be restricted by a flow resistance of the porous structure. The problem arises when there is a significant flow resistance of the porous structure to exhaust the air out of the lumen. As long as there is a pressure gradient from the lumen to the outside of the hollow fibre, a flow of gas through the structure will take place, and a lumen pressure gradient from the entrance point of the hollow fibre into the vacuum system will be observed. Additionally, this distance gradient of the local lumen pressure cannot be determined in a straightforward manner. In case of plasma modification of the outer surface and the inner porous structure, an opposite flow of gas, not from the inside to the outside of the porous structure, but a flow and diffusion of activated gas from the outside towards the lumen side is necessary.